CBP-1/p300 acetyltransferase regulates SKN-1/Nrf cellular levels, nuclear localization, and activity in C. elegans

SKN-1/Nrf transcription factors regulate diverse biological processes essentially stress defense, detoxification, and longevity. Studies in model organisms have identified a broad range of regulatory processes and mechanisms that profoundly influence SKN-1/Nrf functions. Defining the mechanisms how SKN-1 is regulated will provide insight how cells defend against diverse stressors contributing to aging and disease. In this study, we demonstrate a crucial role for the acetyltransferase CBP-1, the C. elegans homolog of mammalian CREB-binding protein CBP/p300 in the activation of SKN-1. cbp-1 is essential for tolerance of oxidative stress and normal lifespan. CBP-1 directly interacts with SKN-1 and increases SKN-1 protein abundance. In particular CBP-1 modulates SKN-1 nuclear translocation under basal conditions and in response to stress and promotes SKN-1-dependent transcription of protective genes. Moreover, CBP-1 is required for SKN-1 nuclear recruitment, transcriptional activity, and longevity due to reduced insulin/IGF-1-like signaling, mTOR-, and GSK-3 signaling. Our findings establish the acetyltransferase CBP-1 as a critical activator of SKN-1 that directly modulates SKN-1 protein stability, nuclear localization, and function to ascertain normal stress response and lifespan.